With 17,000 new cases diagnosed each year in the U.S. or an annual incidence of 5.3/100,000 population, malignant gliomas account for about 80% of all primary malignant brain tumors, and 82% of these cases are classified as the WHO grade IV tumor—glioblastoma multiform (GBM) (Ostrom et al, 2013). The median survival time of GBM patients from diagnosis with treatment is only about 15 months. Without treatment, most GMB patients survive for only a few months (Sowers et al, 2014). Malignant gliomas are characterized by rapid growth and diffuse aggressive invasion within the brain, leading to a variety of debilitating neurological and psychiatric symptoms, such as nausea and vomiting, aphasia, hemispatial neglect, visual field defect, cognition changes, gait imbalance, urinary incontinence, blurred vision, headache, memory loss, hemiparesis, and personality changes.
Due to the restriction of infiltration by the blood-brain barrier of most anti-tumor drugs into the central nervous system (CNS), the standard treatment for malignant gliomas is limited to surgical resection followed by conventional radiotherapy in combination with temozolomide (Bernardi et al, 2009). However, the overall outcome of surgical treatment for gliomas is often compromised by the complexity of intracranial operation, extent of resection, and residual tumor cells that can cause tumor recurrence with a relatively short relapse time. Moreover, there are many cases where surgical ablation is not an option due to tumor location, tumor size and/or poor patient performance status. In addition, glioma cells, especially those in recurrent glioblastomas, have proven to be extremely resistant to conventional chemotherapy and radiotherapy. All these unfortunate factors together make gliomas the most difficult to treat as well as the most lethal of the malignant brain tumors. Developing new therapeutics for this devastating neurological condition is an urgent and unmet need.
Although the molecular mechanisms underlying gliomagenesis are poorly understood, growing evidence from studies on animal models and human patients suggests that cyclooxygenase-2 (COX-2) might be involved in the development of gliomas (Xu et al, 2014; Qiu et al, 2017). COX-2 is commonly overexpressed in gliomas, and its expression level is highly positively correlated with the tumor grade. As a major enzymatic product of COX-2, prostaglandin E2 (PGE2) mediates inflammatory processes within the brain and facilitates the progression of many chronic inflammation-associated neurological diseases via its four downstream receptors—EP1, EP2, EP3, and EP4. EP1 receptor is a Gαq-coupled to mediate the mobilization f cytosolic Ca2+ and activation of protein kinase C (PKC); EP2 and EP4 are linked to Gαs that activiates adenylyl cyclase, resulting in the synthesis of cAMP (Jiang and Dingledine, 2013a). PGE2 has been proposed to cause tumorigenesis through all four EP receipts (Payner et al, 2006; Wang and Dubois, 2010; Jiang and Dingledine, 2013a). The present investigators, as well as others, previously demonstrated that PGE2 via EP2 promotes tumor cell survival, proliferation, angiogenesis and inflammation in several types of tumors including, for example, those in the colon, skin, breast, and prostate. However, to date, the identity of the EP receptor that directly mediates the development and progression of gliomas has been unknown. Identification of the EP receptor is critical for developing appropriately targeted therapeutics for this devastating disease.